Schizophrenia is believed to be a neurodevelopmental disorder with synaptic abnormalities. Deficits in dopaminergic and GABAergic synaptic transmission have been associated with schizophrenia. Our long-term goal is to investigate molecular and cellular mechanisms of neurological disorders and identify novel drug target for therapeutic treatment. This proposal will study the function of neuroligin-2 (NL-2) mutations identified from schizophrenia patients. NL-2 is a cell adhesion molecule, localized specifically at inhibitory synaptic sites. Our own studies, together with others, demonstrate that NL-2 plays a critical role in promoting GABAergic synaptogenesis. Previous work had identified mutations of neuroligin-3 and neuroligin-4 in autism patients. Here, we report the identification of 4 NL-2 mutations (644A, 1528A, 1862A, and 1909A) from 400 schizophrenia patients, but none from 400 healthy controls, by our collaborators Dr. Chia-Hsiang Chen and colleagues. We performed functional analysis on one NL-2 mutant 644A using our molecularly engineered GABAergic synapse system, and discovered strong defect in promoting GABAergic synapse formation. Based on this exciting finding, this proposal will: 1) Further investigate the functional consequences of all 4 NL-2 mutations on GABAergic synapse formation in heterologous synapse system, as well as in cortical neurons; 2) Establish a novel transgenic mouse model for schizophrenia and related neurodevelopmental disorders. Completion of this proposal will unveil a novel link between NL-2 mutations and schizophrenia, and provide a potential transgenic animal model for studying mental disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating mental illness afflicting about 1 percent of world populations. We report the identification of 4 neuroligin-2 mutations from schizophrenia patients, and pilot studies on one such mutant (644A) revealed functional deficit in promoting GABAergic synapse formation. This proposal will investigate the functional relationship between neuroligin-2 mutations and schizophrenia, and provide a novel transgenic mouse model for further studying schizophrenia and related disorders.